HK1131140B - Substituted prolinamides, and the use thereof - Google Patents

Description

Substituted prolinamides, and uses thereof

The invention relates to novel substituted prolinamides of general formula (I) having valuable properties

Tautomers, enantiomers, diastereomers, mixtures and salts thereof, especially physiologically acceptable salts thereof with inorganic or organic acids or bases.

The compounds of the general formula (I) above, and their tautomers, enantiomers, diastereomers, mixtures and salts, especially their physiologically acceptable salts with inorganic or organic acids or bases, and their stereoisomers, have valuable pharmacological properties, especially an antithrombotic activity and a factor Xa-inhibiting activity.

The present application relates to the above novel compounds of general formula (I), processes for their preparation, pharmaceutical compositions containing pharmacologically effective compounds, processes for their preparation and uses thereof.

A first embodiment of the invention comprises compounds of the general formula (I), in which

D represents a substituted bicyclic ring system of formula

Or

Wherein

K¹

Represents a chemical bond, or-CH₂、-CHR^7a、-CR^7bR^7cOr a group-C (O), wherein

R^7a/R^7b/R^7c

Each independently of the others represents a fluorine atom, a hydroxyl group, C_1-5Alkoxy, amino, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino, C_3-5-cycloalkylideneimino, C_1-5-alkylcarbonylamino, C which may be substituted by 1 to 3 fluorine atoms_1-5-alkyl, hydroxy-C_1-5Alkyl radical, C_1-5-alkoxy-C_1-5Alkyl, amino-C_1-5Alkyl radical, C_1-5-alkylamino-C_1-5Alkyl, di- (C)_1-5-alkyl) -amino-C_1-5Alkyl radical, C_4-7-cycloalkylidenimino-C_1-5-alkyl, carboxyradical-C_0-5Alkyl radical, C_1-5-alkoxycarbonyl-C_0-5Alkyl, aminocarbonyl-C_0-5Alkyl radical, C_1-5-alkylaminocarbonyl-C_0-5Alkyl, di- (C)_1-5-alkyl) -aminocarbonyl-C_0-5-alkyl or C_4-7-cycloalkyleneiminocarbonyl-C_0-5-an alkyl group,

wherein, unless-C (R)^7bR^7c) -corresponds to-CF₂Radicals, otherwise two radicals R^7b/R^7cNot all being bound to a ring carbon atom via a heteroatom at the same time, or

R^7aRepresents fluorine-, chlorine-, bromine-, methyl-, methoxy-, amino-or nitro-substituted phenyl or monocyclic heteroaryl, or

Two radicals R^7b/R^7cTogether with the ring carbon atoms, may form a 3-, 4-, 5-, 6-or 7-membered saturated carbocyclic group or cyclopentene, cyclohexene, oxetane (oxolan), azetidine, thietane (thietan), tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, thietane (pentamethylene sulfide), hexamethyleneimine (hexamethyleneimine), 1, 3-dioxolane, 1, 4-dioxane, hexahydropyridazine, piperazine, thiomorpholine, morpholine, 2-imidazolidinone, 2-oxazolidinone, tetrahydro-2 (1H) -pyrimidinone or [1.3 ] pyrimidinone]Oxazacyclohexan-2-one ([ 1.3)]oxazinan-2-one) ring,

wherein the methylene group may be substituted by 1-2C_1-3-alkyl or CF₃-is substituted by a group, and/or

If the methylene group is not bound to a heteroatom, the methylene group may be substituted by 1 to 2 fluorine atoms, and/or

In which the-CH adjacent to the N atom (radicals)₂The radicals being displaceable by-CO groups, and/or

Wherein the imino groups may each be substituted by C_1-3-alkyl or C_1-3-alkylcarbonyl substitution, and/or

Wherein the sulfur atom may be oxidized to form a sulfoxide or sulfone group,

K²and K³

Each independently of the other represents-CH₂、-CHR^8a、-CR^8bR^8cOr a group-C (O), wherein

R^8a/R^8b/R^8c

Each independently of the other represents C_1-5Alkyl, which may be substituted by 1 to 3 fluorine atoms, hydroxy-C_1-5Alkyl radical, C_1-5-alkoxy-C_1-5Alkyl, amino-C_1-5Alkyl radical, C_1-5-alkylamino-C_1-5Alkyl, di- (C)_1-5-alkyl) -amino-C_1-5Alkyl radical, C_4-7-cycloalkylidenimino-C_1-5Alkyl, carboxy-C_0-5Alkyl radical, C_1-5-alkoxycarbonyl-C_0-5Alkyl, aminocarbonyl-C_0-5Alkyl radical, C_1-5-alkylaminocarbonyl-C_0-5Alkyl, di- (C)_1-5-alkyl) -aminocarbonyl-C_0-5-alkyl or C_4-7-cycloalkyleneiminocarbonyl-C_0-5-an alkyl group,

or two radicals R^8b/R^8cTogether with the ring carbon atoms, may form a 3-, 4-, 5-, 6-or 7-membered saturated carbocyclic group or cyclopentene, cyclohexene, oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran, piperidine, thiacyclohexane, hexamethyleneimine, hexahydropyridazine, tetrahydro-2 (1H) -pyrimidinone, [1.3]An oxazacyclohexan-2-one ring,

wherein the methylene group may be substituted by 1-2C_1-3-alkyl or CF₃-is substituted by a group, and/or

If the methylene group is not bound to a heteroatom, the methylene group may be substituted by 1 to 2 fluorine atoms, and/or

In which-CH is adjacent to the nitrogen atom₂The radicals being displaceable by-CO groups, and/or

Wherein the imino groups may each be substituted by C_1-3-alkyl or C_1-3-alkylcarbonyl substitution, and/or

Wherein the sulfur atom may be oxidized to form a sulfoxide or sulfone group,

with the proviso that in formula (I) R^8bOr R^8cThe heteroatom introduced cannot be separated from X by only one carbon atom, and

in total, there may be no more than 4R selected from^7a、R^7b、R^7c、R^8a、R^8bAnd R^8cA group of (A), and

x represents an oxygen or sulfur atom, CF₂Sulfoxide (sulphoxide), sulfone or NR¹Group (a) in which

R¹Represents a hydrogen atom or a hydroxyl group, C_1-3Alkoxy, amino, C_1-3Alkylamino, di- (C)_1-3-alkyl) -amino, C_1-5Alkyl radical, C_2-5-alkenyl-CH₂、C_2-5-alkynyl-CH₂、C_3-6-cycloalkyl, C_4-6Cycloalkenyl, oxetan-3-yl, tetrahydrofuran-3-yl, benzyl, C_1-5-alkyl-carbonyl, trifluoromethylcarbonyl, C_3-6-cycloalkyl-carbonyl, C_1-5-alkyl-sulfonyl, C_3-6-cycloalkyl-sulfonyl, aminocarbonyl, C_1-5-alkylaminocarbonyl, di- (C)_1-5-alkyl) -aminocarbonyl, C_1-5Alkoxycarbonyl, C_4-7-a cycloalkyleneiminocarbonyl group,

wherein methylene or methyl groups present in the above radicals may additionally be replaced by C if not directly attached to a heteroatom selected from O, N or S_1-3Alkyl, carboxyl, C_1-5-an alkoxycarbonyl group substitution,

or may be substituted by hydroxy, C_1-5Alkoxy, amino, C_1-5-alkylamino radical, C_1-5-dialkylamino or C_4-7-a cycloalkylidene imino group substitution,

and/or methylene or methyl if not directly attached to a heteroatom selected from O, N or S, 1 to 3 hydrogen atoms may be replaced by fluorine atoms,

and wherein

A¹Represents N or CR¹⁰，

A²Represents N or CR¹¹，

A³Represents N or CR¹²，

Wherein R is¹⁰、R¹¹And R¹²Each independently of the other represents:

hydrogen, fluorine, chlorine, bromine or iodine atom, or C_1-5-alkyl, CF₃、C_2-5-alkenyl, C_2-5-alkynyl, cyano, carboxy, C_1-5Alkoxycarbonyl, hydroxy, C_1-3-alkoxy, CF₃O、CHF₂O、CH₂FO, amino, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino or C_4-7-cycloalkylideneimino, and

-L-E-G-J-represents a-C or-C ═ C-C group, which may be substituted by R⁴And R⁵Is substituted, and

R³represents a hydrogen atom or C_1-3-alkyl, and

R⁴represents a hydrogen atom or

Straight or branched C_1-6Alkyl radical, C_2-6-alkenyl or C_2-6-an alkynyl group,

wherein the straight chain or the branched chain C_1-6Alkyl radical, C_2-6-alkenyl or C_2-6-the hydrogen atoms of the methylene and/or methyl segments of the alkynyl group are optionally replaced in whole or in part by fluorine atoms, and/or

Wherein the straight chain or the branched chain C_1-6Alkyl radical, C_2-6-alkenyl or C_2-6-the hydrogen atoms of the methylene and/or methyl segments of the alkynyl group are optionally each independently of the otherIndependently substituted with 1 to 2 substituents selected from: c_3-5Cycloalkyl, nitrile, hydroxy or C_1-5-alkoxy, wherein C_1-5-the hydrogen atoms of the alkoxy groups being optionally replaced in whole or in part by fluorine atoms, allyloxy, propargyloxy, benzyloxy, C_1-5-alkylcarbonyloxy, C_1-5-alkoxycarbonyloxy, carboxy-C_1-5-alkoxy, C_1-5-alkoxycarbonyl-C_1-5Alkoxy, mercapto, C_1-5Alkylthio radical, C_1-5-alkylsulfinyl, C_1-5-alkylsulfonyl, carboxy, C_1-5Alkoxycarbonyl, aminocarbonyl, C_1-5-alkylaminocarbonyl, di- (C)_1-5-alkyl) -aminocarbonyl, C_4-7Cycloalkyleneiminocarbonyl, aminosulfonyl, C_1-5-alkylaminosulfonyl, di- (C)_1-5-alkyl) -aminosulfonyl, C_4-7-cycloalkylidenimosulfonyl, amino, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino, C_1-5-alkylcarbonylamino, C_1-5-alkylsulfonylamino, N- (C)_1-5-alkylsulfonyl) -C_1-5-alkylamino radical, C_3-6Cycloalkylcarbonylamino or morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the carbocyclic and heterocyclic groups in the above rings may each be substituted by 1 to 4C_1-3-alkyl or C_1-3Alkylcarbonyl or substituted by 1-2 oxo groups, and/or

Wherein the straight chain or the branched chain C_2-6-sp of alkenyl²-the hydrogen atoms of the hybridized carbon atoms are optionally replaced in whole or in part by fluorine atoms, or

Nitrile, carboxyl, aminocarbonyl, C_1-5-alkylaminocarbonyl radical, C_3-6Cycloalkylaminocarbonyl, di- (C)_1-5-alkyl) -aminocarbonyl, C_1-5-alkoxycarbonyl or C_4-7Cycloalkyleneiminocarbonyl, in which the methylene group is optionally substituted by oxygen, sulphur or by C_0-3Replacement of the nitrogen atom by an alkyl group, or

Phenyl, mono-or bicyclic heteroarylphenyl-C_1-5Alkyl or mono-or bicyclic heteroaryl-C_1-5-an alkyl group,

optionally mono-to trisubstituted in the phenyl or heteroaryl moiety by identical or different substituents selected from the group consisting of: fluorine, chlorine, bromine and iodine atoms, and C_1-5Alkyl, trifluoromethyl, amino, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino, hydroxy, C_1-5-alkoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy, carboxyl and C_1-5-alkoxycarbonyl, and

if-L-E-G-J-represents a-C-C-C-C group, R at E or G⁴May also represent fluorine atom or hydroxyl, methoxy, C_3-5-alkenyl-oxy, C_3-5-alkynyloxy, C_2-5-alkoxy, C_3-6-cycloalkyl-oxy, C_1-5-alkylaminocarbonyloxy, di- (C)_1-5-alkyl) -aminocarbonyloxy or C_4-7-cycloalkylideminocarbonyloxy, phenyl-C_0-3Alkoxy, heteroaryl-C_0-3Alkoxy, amino, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino, C_4-7-cycloalkylideneimino, C_1-3-acylamino group, (C)_1-3-acyl group) C_1-3-alkylamino radical, C_1-5-alkoxycarbonylamino, C_1-5-alkylaminocarbonylamino, di- (C)_1-5-alkyl) -aminocarbonylamino or C_4-7-a cycloalkyleneiminocarbonylamino group,

wherein the methyl or methylene groups present in the above alkyl or cycloalkyl groups may each be substituted independently of one another by substituents selected from the group consisting of: morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, dimethylaminocarbonyl, C_1-5Alkoxycarbonyl, carboxyl, methyl, hydroxyl, methoxy or amino, and

the above phenyl or heteroaryl groups are optionally mono-to trisubstituted by the same or different substituents selected from the group consisting of: fluorine, chlorine, bromine and iodine atoms, and C_1-5-alkyl, trifluoromethyl,Amino group, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino, hydroxy, C_1-5-alkoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy, carboxyl and C_1-5-an alkoxycarbonyl group, a carbonyl group,

with the proviso that the following are excluded:

two hetero atoms selected from oxygen and nitrogen being substituted by exactly one CH₂The radicals being separate from one another, and/or

The two atoms form a-O-O or-S-O-bond;

R⁵represents a hydrogen atom, C_1-5Alkyl radical, C_2-5-alkenyl or C_2-5-alkynyl or phenyl-C_0-5Alkyl, wherein the alkyl may be substituted by hydroxy, methoxy, hydroxycarbonyl or C_1-5-alkoxycarbonyl, or if R⁵Attached to E or G, it may also represent hydroxy or methoxy, or

R⁴And R⁵If they are bound to the same carbon atom, together with the carbon atom, they may form a-C ═ O group or-CF₂A group of, or

R⁴And R⁵If they are attached to the same carbon atom or two adjacent carbon atoms, they together with said carbon atoms may form a 3-7-membered carbocyclic group or a monounsaturated 5-7 membered carbocyclic group,

wherein one of the carbon chain members of the cyclic group may be interrupted by an oxygen or sulfur atom or-NH, -N (C)_1-5-alkyl), -N (C)_1-4Alkylcarbonyl) or carbonyl, sulfinyl or sulfonyl substitution, and/or

These C_4-7Two directly adjacent carbon chain members in a carbocyclyl group may be taken together by-C (O) NH, -C (O) N (C)_1-5-alkyl), -S (O)₂NH or-S (O)₂N(C_1-5-alkyl) group replacement, and/or

These C_5-7Four directly adjacent carbon chain members in a carbocyclyl group may be taken together by-O-CH₂-CH₂-O group replacement, and/or

1 to 3 carbon atoms of these 3-7-membered ring groups are in each case optionally substituted independently of one another by: 1 or 2 fluorine atoms or 1 or 2C_1-5Alkyl or hydroxy, formyloxy, C_1-5-alkoxy, C_1-5-alkylcarbonyloxy, amino, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino, C_4-7-cycloalkylideneimino, C_1-5-alkylcarbonylamino, C_3-6-Cycloalkylcarbonylamino, nitrile, carboxy-C_1-5Alkyl radical, C_1-5-alkoxycarbonyl-C_1-5Alkyl, carboxyl, C_1-5Alkoxycarbonyl, aminocarbonyl, C_1-5-alkylaminocarbonyl, di- (C)_1-5-alkyl) -aminocarbonyl or C_4-7-cycloalkyleneiminocarbonyl, with the proviso that R is excluded⁴And R⁵Together form the following cyclic group,

wherein two nitrogen atoms or one nitrogen atom and one oxygen atom in the cyclic group are exactly one optionally substituted CH₂The radicals being separate from one another, and/or

Wherein two atoms in the ring form a-O-O or-S-O-bond,

or fragments thereof

Represents a group

R¹³Represents a hydrogen atom or C_1-5-an alkyl group,

m represents optionally substituted R²And R⁶A substituted benzene, thiophene or pyridine ring, wherein

R²Represents a fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, vinyl, methoxy, ethynyl, cyano or-C(O)NH₂Group (a) and

R⁶represents a hydrogen, fluorine, chlorine, bromine or iodine atom or a hydroxyl, methoxy, trifluoromethoxy, C optionally substituted by a fluorine atom_1-3-alkyl, cyano, amino or NH₂A group of C (O),

wherein, unless otherwise specified, the term "heteroaryl" as referred to in the above definitions refers to monocyclic 5-or 6-membered heteroaryl, wherein

The 6-membered heteroaryl group contains 1, 2 or 3 nitrogen atoms, and

the 5-membered heteroaryl group optionally containing C_1-3Imino substituted by alkyl, or by oxygen or sulfur atoms, or optionally by C_1-3An alkyl-substituted imino group or an oxygen or sulfur atom and additionally 1 or 2 nitrogen atoms, or

Optionally is covered with C_1-3-an alkyl-substituted imino group and three nitrogen atoms,

and furthermore optionally by fluorine, chlorine or bromine atoms, C_1-3-alkyl, hydroxy, C_1-3Alkoxy, amino, C_1-3Alkylamino, di- (C)_1-3-alkyl) -amino or C_3-6-a cycloalkylidenimino-substituted phenyl ring may be fused to the above-mentioned monocyclic heteroaryl group via two adjacent carbon atoms,

the attachment is through a nitrogen or carbon atom of the heterocyclic moiety or fused to the benzene ring,

and wherein, unless otherwise specified, the term "halogen atom" referred to in the above definitions refers to an atom selected from fluorine, chlorine, bromine or iodine,

and unless otherwise specified, the alkyl, alkenyl, alkynyl and alkoxy groups having two or more carbon atoms contained therein in the above definitions may be straight-chain or branched, and the alkyl groups in the above dialkylated groups (e.g., dialkylamino groups) may be the same or different,

and unless otherwise specified, the hydrogen atoms of the methyl or ethyl group contained in the above definition may be replaced in whole or in part by fluorine atoms,

tautomers, enantiomers, diastereomers, mixtures, and salts thereof.

Examples of monocyclic heteroaryl groups are pyridyl, N-oxy-pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1, 2, 3] triazinyl, [1, 3, 5] triazinyl, [1, 2, 4] triazinyl, pyrrolyl, imidazolyl, [1, 2, 4] triazolyl, [1, 2, 3] triazolyl, tetrazolyl, furyl, isoxazolyl, oxazolyl, [1, 2, 3] oxadiazolyl, [1, 2, 4] oxadiazolyl, furazanyl, thienyl, thiazolyl, isothiazolyl, [1, 2, 3] thiadiazolyl, [1, 2, 4] thiadiazolyl or [1, 2, 5] thiadiazolyl.

Examples of bicyclic heteroaryls are benzimidazolyl, benzofuranyl, benzo [ c ] furanyl, benzothienyl, benzo [ c ] thienyl, benzothiazolyl, benzo [ c ] isothiazolyl, benzo [ d ] isothiazolyl, benzoxazolyl, benzo [ c ] isoxazolyl, benzo [ d ] isoxazolyl, benzo [1, 2, 5] oxadiazolyl, benzo [1, 2, 5] thiadiazolyl, benzo [1, 2, 3] thiadiazolyl, benzo [ d ] [1, 2, 3] triazinyl, benzo [1, 2, 4] triazinyl, benzotriazolyl, cinnolinyl, quinolinyl, N-oxy-quinolinyl, isoquinolinyl, quinazolinyl, N-oxy-quinazolinyl, quinoxalinyl, phthalazinyl, indolyl, isoindolyl, or 1-oxa-2, 3-diaza-indenyl.

C as mentioned in the above definition_1-6Examples of-alkyl are methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-dimethyl-3-butyl or 2, 3-dimethyl-2-butyl.

C as mentioned in the above definition_1-5Examples of alkoxy are methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, sec-butoxy, tert-butoxyOxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy or neopentyloxy.

C as mentioned in the above definition_2-5Examples of alkenyl are vinyl, 1-propen-1-yl, 2-propen-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3-buten-1-yl, 1-penten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-hexen-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 4-hexen-1-yl, 5-hexen-1-yl, but-1-en-2-yl, but-2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en-1-yl, pent-1-en-2-yl, pent-2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-1-en-3-yl, pent-2-en-3-yl, 2-methyl-but-1-en-1-yl, 2-methyl-but-2-en-1-yl, 2-methyl-but-3-en-1-yl or 2-ethyl-prop-2-en-1-yl.

C as mentioned in the above definition_2-5Examples of alkynyl are ethynyl, 1-propynyl, 2-propynyl, 1-butyn-1-yl, 1-butyn-3-yl, 2-butyn-1-yl, 3-butyn-1-yl, 1-pentyn-1-yl, 1-pentyn-3-yl, 1-pentyn-4-yl, 2-pentyn-1-yl, 2-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 2-methyl-1-butyn-4-yl, 3-methyl-1-butyn-1-yl or 3-methyl-1-butyn-3-yl.

A second embodiment of the invention comprises compounds of formula (I), wherein E, G, J, L, M, R³-R⁵And R¹³Is as defined in embodiment 1, and wherein

D represents a substituted bicyclic ring system of formula

Or

Wherein

K¹

represents-CH₂、-CHR^7a、-CR^7bR^7cOr a group-C (O), and wherein

R^7a/R^7b/R^7c

Each independently of the others represents a fluorine atom, a hydroxyl group, C_1-5-alkoxy, C_1-5-an alkyl group,

wherein, unless-C (R)^7bR^7c) -corresponds to-CF₂Radicals, otherwise two radicals R^7b/R^7cNot all being bound to a ring carbon atom via a heteroatom at the same time, or

Two radicals R^7b/R^7cTogether with the ring carbon atoms may form a 3-membered carbocyclic group, an

K²And K³

Each independently of the other represents-CH₂、-CHR^8a、-CR^8bR^8cOr a group-C (O), wherein

R^8a/R^8b/R^8c

Each independently of the other represents C_1-5-alkyl, and/or

Two radicals R^8b/R^8cTogether with the ring carbon atoms may form a 3-membered saturated carbocyclic group, an

In total, there may be no more than 4R selected from^7a、R^7b、R^7c、R^8a、R^8bAnd R^8cA group of

X represents an oxygen or sulfur atom, a sulfoxide, a sulfone, -CF₂-or NR¹Group (a) in which

R¹Represents a hydrogen atom or a hydroxyl group, C_1-3Alkoxy, amino, C_1-3Alkylamino, di- (C)_1-3-alkyl) -amino, C_1-5Alkyl radical, C_2-5-alkenyl-CH₂、C_2-5-alkynyl-CH₂Or C_3-6-a cycloalkyl group,

and wherein

A¹Represents N or CR¹⁰，

A²Represents N or CR¹¹，

A³Represents N or CR¹²，

Wherein R is¹⁰、R¹¹And R¹²Each independently of the other represent

Hydrogen, fluorine, chlorine, bromine or iodine atom, or C_1-5-alkyl, CF₃Cyano, carboxyl, C_1-5Alkoxycarbonyl, hydroxy, C_1-3-alkoxy, CF₃O、CHF₂O、CH₂FO, amino, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino or C_4-7-cycloalkylideneimino.

A third embodiment of the present invention includes those compounds of embodiments 1 or 2 wherein E, G, J, L, M, R³-R⁵、R¹³、D、K¹、K²And K³Is as defined in the first or second embodiment, and wherein

X represents NR¹Group (a) in which

R¹Represents a hydrogen atom or C_1-5-alkyl, allyl or cyclopropyl, and

A¹represents CR¹⁰，

A²Represents CR¹¹，

A³Represents N or CR¹²，

Wherein R is¹⁰、R¹¹And R¹²Each independently of the other represents:

hydrogen, fluorine or chlorine atoms, or methyl, CF₃Cyano, carboxyl, C_1-5Alkoxycarbonyl, hydroxy, methoxy, CF₃O、CHF₂O、CH₂FO group.

A fourth embodiment of the present invention includes those compounds of formula (I) wherein D, E, G, J, L, M, R³And R¹³Is as defined in embodiment 1, 2 or 3, and wherein

R⁴Represents a hydrogen atom or

Straight or branched C_1-6-an alkyl group,

wherein the straight chain or the branched chain C_1-6-the hydrogen atoms of the methylene and/or methyl segments of the alkyl radical are optionally replaced in whole or in part by fluorine atoms, and/or

Wherein the straight chain or the branched chain C_1-6-the hydrogen atoms of the methylene and/or methyl fragment of the alkyl group are optionally each independently substituted by a substituent selected from the group consisting of: hydroxy, C_1-5Alkoxy, carboxyl, C_1-5Alkoxycarbonyl, aminocarbonyl, C_1-5-alkylaminocarbonyl, di- (C)_1-5-alkyl) -aminocarbonyl, C_4-7-cycloalkylidenocarbonyl, amino, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino, C_1-5-alkylcarbonylamino, C_1-5-alkylsulfonylamino, N- (C)_1-5-alkylsulfonyl) -C_1-5-alkylamino radical, C_3-6-cycloalkylcarbonylamino, or

Nitrile, carboxyl, aminocarbonyl, C_1-5-alkylaminocarbonyl radical, C_3-6Cycloalkylaminocarbonyl, di- (C)_1-5-alkyl) -aminocarbonyl, C_1-5-alkoxycarbonyl or C_4-7Cycloalkyleneiminocarbonyl, in which the methylene group is optionally substituted by oxygen, sulphur or by C_0-3Replacement of the nitrogen atom by an alkyl group,

and is

if-L-E-G-J-represents a-C-C-C-C group, R at E or G⁴May also represent fluorine atom or hydroxyl, methoxy, C_3-5-alkenyloxy, C_3-5-alkynyloxy, C_2-5-alkyl-oxy, C_3-6-cycloalkyl-oxy, C_1-5-alkylaminocarbonyloxy, di (C)_1-5-alkyl) aminocarbonyloxy or C_4-7Cycloalkyleneiminocarbonyloxy, phenyl-C which may be substituted in the phenyl ring by 1-2 fluorine atoms or by methoxy_0-2Alkoxy, amino, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino, C_4-7-cycloalkylideneimino, C_1-3-acylamino group, (C)_1-3-acyl group) C_1-3-alkylamino radical, C_1-5-alkoxycarbonylamino, C_1-5-alkylaminocarbonylamino, di (C)_1-5-alkyl) aminocarbonylamino or C_4-7-a cycloalkyleneiminocarbonylamino group,

wherein the methyl or methylene groups present in the above alkyl or cycloalkyl groups may each be substituted independently of one another by substituents selected from the group consisting of: dimethylaminocarbonyl, C_1-5Alkoxycarbonyl, carboxyl, methyl, hydroxyl, methoxy or amino,

provided that the following cases are excluded

CH in which the two heteroatoms selected from oxygen and nitrogen are exactly one optionally substituted₂The radicals being separate from one another, and/or

Said two atoms forming a-O-O or-S-O-bond, and

R⁵represents a hydrogen atom or C_1-5-alkyl, allyl, propargyl or benzyl, or if R⁵Attached to E or G, it may also represent hydroxy or methoxy, or

R⁴And R⁵If they are bound to the same carbon atom, together with the carbon atom, they may form a-C ═ O group or-CF₂A group of, or

R⁴And R⁵If they are attached to the same carbon atom or two adjacent carbon atoms, together with said carbon atoms they may form a 3-to 7-membered carbocyclic group,

wherein one of the carbon chain members of the cyclic group may be substituted by an oxygen or sulfur atom or-NH、-N(C_1-5-alkyl), -N (C)_1-4Alkylcarbonyl) or carbonyl, sulfinyl or sulfonyl substitution, and/or

These C_4-7Two directly adjacent carbon chain members in a carbocyclyl group may be taken together by-C (O) NH, -C (O) N (C)_1-5-alkyl), -S (O)₂NH or-S (O)₂N(C_1-5-alkyl) substitution, and/or

These C_5-7Four directly adjacent carbon chain members in a carbocyclyl group may be taken together by-O-CH₂-CH₂The substitution of the O group is carried out,

with the proviso that R is excluded⁴And R⁵Together form the following cyclic group,

CH in which exactly one of the two nitrogen atoms or one of the nitrogen and one of the oxygen atoms of the cyclic group is optionally substituted₂The radicals being separate from one another, and/or

Wherein two atoms in the ring form a-O-O or-S-O-bond.

A fifth embodiment of the present invention includes those compounds of embodiments 1, 2, 3 or 4 wherein D, M, R³And R¹³Is as defined in embodiment 1, 2, 3 or 4, and wherein

-L-E-G-J-represents a-C-C-C-C group, which may be substituted by R⁴And R⁵Substituted, R⁴And R⁵Is as defined above in embodiments 1, 2, 3 or 4.

A sixth embodiment of the present invention includes those compounds of embodiments 1, 2, 3, 4 or 5 wherein

D represents a substituted bicyclic ring system of the formula

Or

Wherein

K¹represents-CH₂、-CHR^7a、-CR^7bR^7cOr a group-C (O), wherein

R^7aIs represented by C_1-2Alkyl radical, and

R^7b/R^7ceach independently of the others represents hydroxy, methoxy or C_1-3-an alkyl group,

in which two radicals R^7b/R^7cNot bound to a ring carbon atom via an oxygen atom at the same time, or two radicals R^7b/R^7cTogether with the ring carbon atoms may form a 3-membered carbocyclic group, an

K²And K³In each case independently of one another denotes-CH₂、-CHR^8aor-CR^8bR^8cGroup (a) in which

R^8a/R^8b/R^8c

Each independently of the other represents C_1-3-alkyl, and/or

Two radicals R^8b/R^8cTogether with the ring carbon atoms may form a 3-membered saturated carbocyclic group, an

In total, there may be no more than 4R selected from^7a、R^7b、R^7c、R^8a、R^8bAnd R^8cAnd X represents NR¹Group (a) in which

R¹Represents a hydrogen atom or C_1-3-alkyl, allyl or cyclopropyl, and

A¹represents CR¹⁰，

A²Represents CR¹¹，

A³Represents CR¹²，

Wherein R is¹⁰、R¹¹And R¹²Each independently of the other represents:

hydrogen, fluorine or chlorine atoms, or methyl, CF₃Hydroxy, methoxy, CF₃O、CHF₂O、CH₂The radical FO is a radical of,

and is

-L-E-G-J-represents a-C-C-C-C group, which may be substituted by R⁴And R⁵Is substituted, and

R³represents a hydrogen atom, an

R⁴Represents a hydrogen atom or

Straight or branched C_1-3-an alkyl group,

wherein the straight chain or the branched chain C_1-6-the hydrogen atoms of the methylene and/or methyl fragments of the alkyl group are optionally substituted independently of each other by substituents selected from the group consisting of: hydroxy, C_1-5Alkoxy, carboxyl, C_1-5-alkoxycarbonyl, or

R⁴If attached to E or G, it may also represent a fluorine atom or a hydroxyl, methoxy, C_3-5-alkenyl-oxy, C_2-5-alkyl-oxy, C_3-6-cycloalkyl-oxy, C_1-5-alkylaminocarbonyloxy, di (C)_1-5-alkyl) aminocarbonyloxy or C_4-7-a cycloalkyleneiminocarbonyloxy group,

under the condition that the following cases are excluded

Said CH with exactly one heteroatom selected from oxygen and nitrogen being optionally substituted₂The radicals being separate from one another, and

R⁵represents a hydrogen atom or C_1-5-alkyl, allyl or benzyl, or if R⁵If attached to E or G, it may also represent hydroxy or methoxy, or

R⁴And R⁵If they are bound to the same carbon atom, they may form together with the carbon atom-C ═ O group or-CF₂A group of, or

R⁴And R⁵If they are attached to the same carbon atom or two adjacent carbon atoms, together with said carbon atoms they may form a 3-to 6-membered carbocyclic group,

wherein these C_5-6Four directly adjacent carbon chain members in a carbocyclyl group may be taken together by-O-CH₂-CH₂The substitution of the O group is carried out,

R¹³represents a hydrogen atom, and is represented by,

m denotes the radical R in the 4 position²Substituted benzene rings or by R in position 5²A substituted pyridine ring, wherein R²Represents a fluorine, chlorine, bromine atom, methoxy group or ethynyl group, and

R⁶represents a hydrogen or fluorine atom.

A seventh embodiment of the present invention includes those compounds of embodiments 1, 2, 3, 4, 5 or 6 wherein D, R³、R¹³And M is as defined above, and wherein the central ring

To representOr

An eighth embodiment of the present invention includes those compounds of embodiments 1, 2, 3, 4, 5, 6 or 7 wherein

D represents a substituted bicyclic ring system of the general formula:

a ninth embodiment of the present invention includes those compounds of embodiments 1, 2, 3, 4, 5, 6, 7 or 8 which are in the R configuration at chain members G and L of the 5-membered central ring.

The compounds of general formula (I) according to the invention are obtained by methods known per se (for example by the following methods):

(a) the preparation of compounds of the general formula (IIa) or (IIb) is described in the examples or can be carried out, for example, according to one of the following schemes 1 and 2 or analogously to the synthetic methods described in WO2004/87695, WO2004/87646 or WO 2003/45912:

wherein A is¹To A³、K¹To K³M and R¹To R⁶As defined in embodiment 1, and which is optionally protected on any amino, hydroxyl, carboxyl or thiol group by customary protecting Groups as described, for example, in t.w. Greene, p.g.m.wuts, Protective Groups in Organic Synthesis, Wiley, 1991 and 1999, and these protecting Groups can be cleaved by methods known from this document.

Scheme 1

Scheme 2

Wherein

Q/Q¹Representing a leaving group or a group convertible in situ thereto, e.g. halogen atom, hydroxy, C_1-4-alkoxy, alkoxycarbonyloxy, 4-nitrophenoxy, trichloromethyl or acyloxy, and PG represents a protecting group known from the literature for amino functions, such as tert-butoxycarbonyl, benzyloxycarbonyl or trifluoroacetyl.

The reaction steps i) -iv) shown in schemes 1 and 2 can be carried out in the manner described in the examples or according to conditions known from the literature, for example as follows:

i) acylation of amine (IVa) with optionally activated carboxylic acid (V) or (VI):

the acylation is carried out using the corresponding halide or anhydride, optionally in the presence of an inorganic or organic base, at a temperature of-20 to 200 ℃, however preferably at a temperature of-10 to 100 ℃, in a solvent such as dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, sodium hydroxide solution or sulfolane.

However, the acylation can also be carried out with the free acid, optionally in the presence of an acid activating reagent or a dehydrating agent, optionally with the addition of an auxiliary base such as sodium hydroxide solution, cesium, potassium or sodium carbonate or bicarbonate, or an amine base such as pyridine, triethylamine, N-methylmorpholine or diisopropylethylamine at a temperature of-20 to 200 ℃, however preferably at a temperature of-10 to 160 ℃. Acid activating or dehydrating agents such as ethyl-1-ethoxy-1, 2-dihydroquinoline-1-carboxylate, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, propanephosphonic acid cyclic anhydride (propanephosphonic acid cyclic anhydride), N, N ' -dicyclohexylcarbodiimide/camphorsulfonic acid, N, N ' -dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N, N ' -carbonyldiimidazole, O- (benzotriazol-1-yl) -N, N, N ' -tetramethyl-uronium tetrafluoroborate/N-methylmorpholine, N-methyl-or N, N ' -dimethyluronium tetrafluoroborate, O- (benzotriazol-1-yl) -N, N '-tetramethyl-uronium tetrafluoroborate/N-ethyldiisopropylamine, O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyl-uronium hexafluorophosphate/N-methyl-quinoline, O-pentafluorophenyl-N, N '-tetramethyluronium hexafluorophosphate/triethylamine, N' -thionyldiimidazole or triphenylphosphine/carbon tetrachloride.

Acylation can also be carried out by activation with trimethylaluminum using the carboxylic ester (V) or (VI) with the amine (IVa).

Other methods of amide coupling are for example described by P.D.Bailey, I.D.Collier, K.M.Morgan in "Comprehensive Functional Group interconnections", Vol.5, Seite257ff., Pergamon1995, or also in Houben-Weyl22, Thieme Verlag, 2003 and the references cited therein.

ii) and iii) cleaving the protecting group

Any protecting group used may optionally be subsequently cleaved by hydrolysis in an aqueous solvent (e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water), in the presence of an acid (such as trifluoroacetic acid, hydrochloric acid or sulfuric acid), or in the presence of an alkali metal base (such as lithium hydroxide, sodium hydroxide or potassium hydroxide), or via ether cleavage, e.g. in the presence of trimethyliodosilane, at a temperature of from 0 to 100 ℃, preferably at a temperature of from 10 to 50 ℃.

The benzyl, methoxybenzyl or benzyloxycarbonyl group is however cleaved hydrogenolytically, for example using hydrogen in the presence of a catalyst (e.g. palladium on carbon), in a solvent (e.g. tetrahydrofuran, methanol, ethanol, ethyl acetate, dimethylformamide/acetone or glacial acetic acid), optionally with addition of an acid (e.g. hydrochloric acid), at a temperature of from 0 to 50 ℃, however preferably at ambient temperature, and under a hydrogen pressure of from 1 to 7 bar, however preferably under a hydrogen pressure of from 1 to 5 bar.

However, the protecting groups can also be cleaved as described in T.W.Greene, P.G.M.Wuts in "protective groups in Organic Synthesis", Wiley, 1991 and 1999.

iv) Synthesis of Urea

The reaction of the derivative (VIIa) with the isocyanate (VIII) or the optionally activated carbamic acid IX (such as 4-nitrophenylcarbamate) is carried out at a temperature of-20 to 200 ℃, however preferably at a temperature of-10 to 160 ℃, in a solvent such as water, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide or sulfolane or a mixture of the above-mentioned solvents, optionally with the addition of an auxiliary base, for example sodium hydroxide solution, carbonate or bicarbonate of cesium, potassium or sodium, or an amine base such as pyridine, triethylamine, N-methylmorpholine or diisopropylethylamine.

The compounds of the general formula (IIb) can be synthesized analogously to schemes 1 and 2 starting from component (IVb).

(b) The components of the general formulae (IVa) and (IVb) are known from the literature, or their synthesis is described in embodiments by way of example, or they may be synthesized, for example, by or analogously to synthesis methods known from the literature, as described, for example, in WO 2006/108709; s.durand-Henchoz et al ball.soc.chim.france 1966, 11, 3413; de et al synth. commun.2002, 32, 2555; g.j.qualich et al, j.org.chem.1998, 63, 4116 or in j.d.harling et al synth.commun.2001, 31, 787

Wherein A is¹、A²、A³、K¹、K²、K³X and R³As defined in embodiment 1, and which is optionally protected on any amino, hydroxyl, carboxyl or thiol Groups present by customary protections, as described, for example, in T.W.Greene, P.G.M.Wuts, Protective Groups in Organic Synthesis, Wiley, 1991 and 1999The groups are protected and these protecting groups can be cleaved off during the synthesis sequence for the preparation of the compounds of formula (I) by methods known from this document.

For example, compounds of the general formulae (IVa) and (IVb) (wherein R³Represents a hydrogen atom and A¹、A²、A³、K¹、K²、K³And X is as defined in embodiment 1) can be prepared by reducing the nitro group of compounds of the general formulae (Xa) and (Xb) as follows

Wherein A is¹、A²、A³、K¹、K²、K³And X is as defined in embodiment 1.

The reduction of the nitro group is carried out, for example, in a solvent or solvent mixture (e.g. water, aqueous ammonium chloride solution, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic anhydride), with a metal (e.g. iron, zinc, tin) or a sulfur-containing compound (e.g. ammonium sulfide, sodium sulfide or sodium dithionite), or by catalytic hydrogenation with hydrogen, for example at a pressure of from 0.5 to 100 bar, preferably, however, from 1 to 50 bar, or with hydrazine as reducing agent, suitably in the presence of a catalyst, for example Raney-nickel, palladium-carbon, platinum oxide, platinum or rhodium on mineral fibers, or with a complex hydride, such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride, suitably in a solvent or solvent mixture, such as water, methanol, ethanol, isopropanol, pentane, hexane, cyclohexane, heptane, benzene, toluene, xylene, Ethyl acetate, methyl propionate, glycerol, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, N-methylpyrrolidone or N-ethyl-diisopropylamine, N-C_1-5Alkyl morpholines, N-C_1-5Alkyl piperidines, N-C_1-5Alkylpyrrolidines, triethylamine, pyridine, for example at temperatures of-30 to 250 ℃, but preferably at 0 to 150 ℃.

(c) The components of the general formulae below are known from the literature or their synthesis is described in embodiments by way of example, or they can be prepared, for example, using or analogously to synthesis methods known from the literature, as described, for example, in WO2004/87646, WO2003/45912, WO06/32342 or US2007/0015812

Wherein R is⁴、R⁵、R⁶And R²Is as defined in embodiment 1, and wherein

Q/Q¹Represents, for example, hydroxy or C_1-4Alkoxy, halogen atoms, alkoxycarbonyloxy or acyloxy, which are optionally protected on any amino, hydroxyl, carboxyl or thiol group present by the usual protecting Groups as described, for example, in t.w. greene, p.g. m.wuts, in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and which can be cleaved by methods known from this document during the synthetic sequence for the preparation of compounds of formula (I).

In the reactions described hereinbefore, any reactive groups present, such as hydroxyl, carboxyl, amino, alkylamino or imino groups, may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

Suitable protecting groups for hydroxy groups may be, for example, methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl.

Suitable protecting groups for the carboxyl group may be trimethylsilyl, methyl, ethyl, t-butyl, benzyl or tetrahydropyranyl.

Suitable protecting groups for amino, alkylamino or imino groups can be acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2, 4-dimethoxybenzyl, and there can be phthaloyl for amino.

For example, a suitable protecting group for the ethynyl group may be trimethylsilyl, diphenylmethylsilyl, t-butyldimethylsilyl or 1-hydroxy-1-methyl-ethyl.

Other protecting Groups and their cleavage are described in T.W.Greene, P.G.M.Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999.

The subsequent cleavage of the optionally used protecting group can be carried out, for example, by hydrolysis in an aqueous solvent, for example water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, for example trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of an alkali metal base, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, at a temperature of between 0 and 100 ℃, preferably between 10 and 50 ℃, or by means of ether cleavage, for example in the presence of trimethyliodosilane.

However, benzyl, methoxybenzyl or benzyloxycarbonyl can be cleaved, for example, at a temperature between 0 and 50 ℃, but preferably at ambient temperature, and under a hydrogen pressure of 1 to 7 bar (bar), but preferably 1 to 5 bar, in the presence of a catalyst such as palladium on carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, for example by hydrogenolysis with hydrogen.

The methoxybenzyl group may also be cleaved at a temperature between 0 and 50 ℃, but is preferably cleaved at ambient temperature in a solvent such as dichloromethane, acetonitrile or acetonitrile/water in the presence of an oxidant such as ammonium cerium (IV) nitrate.

The methoxy group is suitably cleaved at a temperature between-35 and-25 ℃ in a solvent such as dichloromethane in the presence of boron tribromide.

The 2, 4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.

The tert-butyl or tert-butoxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as dichloromethane, dioxane or ether.

The phthaloyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at a temperature of between 20 and 50 ℃.

Allyloxycarbonyl is cleaved by treatment with catalytic amounts of tetrakis- (triphenylphosphine) -palladium (0) at a temperature between 0 and 100 ℃, preferably at ambient temperature, under inert gas, preferably in a solvent such as tetrahydrofuran, and preferably in the presence of an excess of a base such as morpholine or 1, 3-dimedone (1, 3-dimedone), or by treatment with catalytic amounts of tris- (triphenylphosphine) -rhodium (I) chloride at a temperature between 20 and 70 ℃ in a solvent such as aqueous ethanol, and optionally in the presence of a base such as 1, 4-diazabicyclo [2, 2, 2] octane.

Furthermore, the obtained compounds of general formula I can be resolved into their enantiomers and/or diastereomers.

Thus, for example, the compounds of the formula I obtained as racemates can be separated into their optical enantiomers in a manner known per se (cf. Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol.6, Wiley Interscience, 1971), and the compounds of the formula I having at least 2 asymmetric carbon atoms can be resolved into their diastereomers on the basis of their physico-chemical differences in a manner known per se (e.g. by chromatography and/or fractional crystallization), and if these compounds are obtained in racemic form, they can subsequently be resolved into the enantiomers in a manner known per se.

The enantiomers are preferably separated by column chromatography on a chiral phase, or by recrystallization from optically active solvents, or by reaction of optically active substances which form salts or derivatives (e.g. esters or amides) with the racemic compound, especially the acids and activated derivatives or alcohols thereof, and the diastereomeric mixtures of the salts or derivatives thus obtained are separated, for example on the basis of their solubility differences, while the free enantiomers can be liberated from the pure diastereomeric salts or derivatives by the action of suitable reagents. Commonly used optically active acids are e.g. tartaric acid in the D-and L-form or dibenzoyltartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. The optically active alcohol can be, for example, (+) -or (-) -menthol, and the optically active acyl group in the amide can be, for example, (+) -or (-) -menthyloxycarbonyl.

Furthermore, the compounds of the formula (I) obtained can be converted with inorganic or organic acids into their salts, especially for pharmaceutical use, into physiologically acceptable salts. Acids which may be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Furthermore, if the novel compounds of the formula (I) contain carboxyl groups, they can, if desired, be converted subsequently with inorganic or organic bases into their salts, especially for pharmaceutical use into their physiologically acceptable salts. Suitable bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

As already mentioned above, the compounds of the general formula (I) and the tautomers, enantiomers, diastereomers and physiologically acceptable salts thereof have valuable pharmacological properties, in particular antithrombotic activity, which is preferably based on an influencing effect on thrombin or factor Xa, for example on an inhibition of thrombin or of factor Xa, on an extension of the aptt time and on an inhibition of the relevant serine proteases, for example urokinase, factor vila, factor IX, factor XI and factor XII.

The inhibitory effect of the compounds listed in the experimental section on factor Xa can be studied as follows:

method of producing a composite material

Enzyme kinetics assays were performed with chromogenic substrates. The amount of p-nitroaniline (pNA) released from the colorless chromogenic substrate by human factor Xa was determined spectrophotometrically at 405 nm. This amount is directly proportional to the activity of the enzyme used. The inhibition of the enzymatic activity by the test substance (relative to the solvent control) is detected with different concentrations of the test substance and the IC is calculated therefrom₅₀It is the concentration at which the factor Xa used is 50% inhibited.

Material

Tris (hydroxymethyl) -aminomethane-buffer (100mMol) and sodium chloride (150mMol), pH8.0 plus 1mg/ml protease-free human albumin fraction V.

Factor xa (calbiochem), specific activity: 217IU/mg, final concentration: 7IU/ml per reaction mixture

Substrate S2765(Chromogenix), final concentration: 0.3mM/l (1KM) per reaction mixture

Test substance: final concentrations were 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 μ Mol/l.

Operation of

Mu.l of a 23.5-fold concentrated starting solution of the test substance or solvent (control), 175. mu.l of TRIS/HSA buffer and 25. mu.l of a 65.8U/L factor Xa working solution were incubated at 37 ℃ for 10 minutes. After addition of 25. mu.l of S2765 working solution (2.82mMol/L), the samples were measured at 405nm with a spectrophotometer (SpectraMax250) for 600 seconds at 37 ℃.

Evaluation of

1. The maximum increase (Δ OD/min) over 21 measurement points was determined.

2. The% inhibition relative to the solvent control was determined.

3. An effect curve (% inhibition vs. substance concentration) is made.

4. By finding the X-value (substance) at 50% inhibition of Y on the dose-response curveMass concentration) determination of IC₅₀。

All tested compounds showed IC less than 100. mu. mol/L₅₀The value is obtained.

The compounds prepared according to the invention are generally well tolerated.

According to their pharmacological profile, the novel compounds and their physiologically acceptable salts are suitable for the prevention and treatment of venous and arterial thrombotic disorders, such as the prevention and treatment of deep leg venous thrombosis, thrombophlebitis, the prevention of reocclusion after bypass surgery or angioplasty (pt (c) a), and the prevention of occlusion by peripheral arterial disease, and the prevention and treatment of pulmonary embolism, disseminated intravascular coagulation and severe sepsis, the prevention and prevention of DVT in patients with COPD exacerbations, the treatment of ulcerative colitis, the prevention and treatment of coronary thrombosis, the prevention of stroke, and the prevention of bypass occlusion.

Furthermore, the compounds of the invention are suitable for antithrombotic support therapy in thrombolytic therapy (e.g. thrombolytic therapy with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase), for preventing prolonged restenosis after pt (c) a, for preventing and treating ischemic events in patients with all forms of coronary heart disease, for preventing metastasis and growth of tumors and inflammatory processes, for example in the treatment of pulmonary fibrosis, for preventing and treating rheumatoid arthritis, for preventing or preventing dependent tissue adhesions and/or scar tissue formation, and for promoting wound healing processes.

The mentioned compounds may also be used as anticoagulants in combination with the preparation, storage, fractionation or use of whole blood, or in invasive therapeutic methods, e.g. for coating stents, prosthetic heart valves and catheters, to reduce the risk of thrombosis.

On the basis of their pharmacological profile, the novel compounds and their physiologically acceptable salts are also suitable for the treatment of Alzheimer's disease and Parkinson's disease. An explanation for this can be seen, for example, from the findings from which it can be concluded that thrombin inhibitors or factor Xa inhibitors are valuable drugs for the treatment of alzheimer's disease and parkinson's disease by inhibiting thrombin formation or thrombin activity. Clinical and experimental studies have shown that neurotoxic mechanisms (e.g. inflammation associated with activation of coagulation cascade proteases) are associated with neuronal death resulting from brain trauma. Various studies have shown that thrombin is involved in neurodegenerative processes, such as those resulting from stroke, repeated bypass surgery or traumatic brain injury. An increase in thrombin activity may not be manifested until several days after the peripheral nerve injury. Thrombin has also been shown in turn to cause neurite retraction, as well as glial proliferation, and apoptosis in primary cultures of neuronal and neuroblastoma cells. (for review see: Neurobiol. aging, 2004, 25(6), 783-. In addition, various in vitro studies of the brains of alzheimer's patients have shown that thrombin plays a role in the pathogenesis of this disease (neurosci. lett., 1992, 146, 152-54). An enrichment of immunoreactive thrombin can be detected in neurite plaques of the brains of alzheimer's patients. In vitro, thrombin has been shown to also function in regulating and stimulating the production of "amyloid precursor protein (APP"), and in the cleavage of APP into fragments that can be detected in amyloid plaques in the brains of Alzheimer's patients. In addition, thrombin-induced microglial activation can be shown to lead to degeneration of nigral dopaminergic neurons in vivo. This result leads to the conclusion that microglial activation triggered by one or more endogenous substances such as, for example, thrombin is involved in neuropathological processes such as dopaminergic neuronal cell death as shown, for example, in parkinson's disease patients (j. neurosci, 2003, 23, 5877-86).

The novel compounds and their physiologically acceptable salts can also be used for the prophylaxis and treatment of arterial vascular diseases in combination therapy with lipid-lowering active substances such as HMG-CoA reductase inhibitors and vasodilators, in particular ACE inhibitors, angiotensin II antagonists, renin inhibitors, beta receptor antagonists, alpha receptor antagonists, diuretics, calcium channel blockers or activators of soluble uridylate cyclase.

The novel compounds and their physiologically acceptable salts can also be used in combination therapy with other anticoagulants, such as unfractionated heparin, low molecular weight heparin, Fondaparinux (Fondaparinux), or direct thrombin inhibitors, such as recombinant hirudin or active site thrombin inhibitors, by increasing the antithrombotic effect.

The novel compounds and their physiologically acceptable salts are used therapeutically in combination with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the coagulation system and recombinant analogues thereof (e.g. protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, Prasugrel (Prasugrel), ticlopidine (Ticlopidin)), with P2T-receptor antagonists (e.g. cagrelor) or with recombinant thromboxane receptor antagonists/synthetase inhibitors (e.g. terbogrel).

The dosage required to achieve the corresponding effect is suitably 0.01 to 3mg/kg, preferably 0.03 to 1.0mg/kg, for intravenous administration, 0.03 to 30mg/kg, preferably 0.1 to 10mg/kg, for oral administration, each 1 to 4 times per day.

To this end, the compounds of formula (I) prepared according to the invention, optionally in combination with other active substances, are formulated into conventional galenic preparations, such as plain or sugar-coated tablets, capsules, powders, suspensions or suppositories, together with one or more inert customary carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof.

The novel compounds and their physiologically acceptable salts can be used therapeutically in combination with: acetylsalicylic acid; platelet aggregationA set inhibitor, such as a fibrinogen receptor antagonist (e.g., abciximab, eptifibatide, tirofiban, roxifiban); physiological activators and inhibitors of the coagulation system and recombinant analogs thereof (e.g., protein C, TFPI, antithrombin); inhibitors of ADP-induced aggregation (e.g., clopidogrel, ticlopidine); p₂A T receptor antagonist (e.g., cangrelor) or a combination geldanine receptor antagonist/synthetase inhibitor (e.g., terbogrel).

Experimental part

The following examples are intended to illustrate the invention without limiting its scope.

The melting points and/or IR, UV,¹H-NMR and/or mass spectrometry. Unless otherwise specified, R_fReady-made silica gel 60F was used as a value₂₅₄TLC plates (e.merck, Darmstadt, cat # 1.05714) were assayed without chamber saturation. R given under the heading alumina_fValue used of off-the-shelf alumina 60F₂₅₄TLC plates (e.merck, Darmstadt, cat # 1.05713) were assayed without chamber saturation. R given under the heading inverse-8 (RP-8)_fThe value is using the ready-made RP-8F₂₅₄TLC plates (e.merck, Darmstadt, cat # 1.15684) were assayed without chamber saturation. The ratios of the eluents given refer to the values by volume of the solvents concerned. For chromatographic purification, a chromatographic column prepared from FirmaMillipore (MATREX) was used^TM35-70 μm). Unless a more detailed description of the configuration is provided, it is not clear whether the product is a pure stereoisomer or a mixture of enantiomers and diastereomers.

HPLC-MS data were obtained under the following conditions:

the method A comprises the following steps:

waters Alliance2690, Waters ZQ2000 Mass spectrometer with diode array Detector 996.

The mobile phases used were:

a: water containing 0.10% trifluoroacetic acid

B: acetonitrile containing 0.8% trifluoroacetic acid

Time (min)% A% B flow rate (ml/min)

0.00 95 5 1.00

0.10 95 5 1.00

3.10 2 98 1.00

The stationary phase used was an X-Terra MS C18 column, 2.5 μm, 4.6 mm. times.30 mm.

The diode array detection is performed in the wavelength range of 210-500 nm.

The method B comprises the following steps:

waters Alliance2695, PDA detector 2996.

The mobile phases used were:

a: water containing 0.13% trifluoroacetic acid

B: acetonitrile

Time (min)% A% B flow rate (ml/min)

0.00 95 5 3.50

0.18 95 5 3.50

2.00 2 98 3.50

2.20 2 98 3.50

The stationary phase used was a Varian Microsorb100C18 column, 3 μm, 4.6 mm. times.30 mm.

The diode array detection is performed in the wavelength range of 210-380 nm.

The method C comprises the following steps:

waters Alliance2695, PDA detector 2996.

The mobile phases used were:

a: water containing 0.1% formic acid

B: acetonitrile containing 0.1% formic acid

Time (min)% A% B flow rate (ml/min)

0.00 95 5 1.60

450 10 90 1.60

The stationary phase used was a YMC-Pack ODS-AQ column, 3 μm, 4.6 mm. times.75 mm.

The method D comprises the following steps:

waters Alliance2695, PDA detector 2996.

The mobile phases used were:

a: water containing 0.1% formic acid

B: acetonitrile containing 0.1% formic acid

Time (min)% A% B flow rate (ml/min)

0.00 95 5 1.60

4.50 10 90 1.60

The stationary phase used was a Zorbax Stab leBond C18 column, 3 μm, 4.6 mm. times.75 mm.

The following abbreviations are used in the test description:

DCM dichloromethane

DIPEA N-ethyl-diisopropylamine

DMF N, N-dimethylformamide

EtOH ethanol

sat, saturated

h hours(s)

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

in i.vac. vacuum

conc. concentrated

min for

NMM N-methyl-morpholine

R_fRetention factor

R_tRetention time

TBTU O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate

TEA Triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

Example 1

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl) -amide

(a) (2R, 4R) -4-methoxy-pyrrolidine-2-carboxylic acid (as the hydrochloride salt)

10.3g (48.9mmol) of 1-tert-butoxy (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylate were dissolved in 50ml of THF, 50ml of 6N hydrochloric acid (300mmol) were added, and the mixture was stirred for 3 hours. The reaction mixture was evaporated to dryness under vacuum.

Yield: 7.89g (quantitative)

C₆H₁₁NO₃(145.16)×HCl

Mass spectrum: (M + H)⁺＝146

(b) (2R, 4R) -1- (4-chloro-phenylcarbamoyl) -4-methoxy-pyrrolidine-2-carboxylic acid

13.5g (87.8mmol) of 4-chlorophenyl isocyanate are added to a mixture of 7.89g (43.9mmol) of (2R, 4R) -4-methoxy-pyrrolidine-2-carboxylic acid hydrochloride in 288ml of 5% aqueous sodium hydrogencarbonate solution and stirred at 80 ℃ for 3 hours. 0.6g of further isocyanate was added and the mixture was stirred for a further 1 hour. The reaction mixture was then cooled and the solids were removed by filtration. The solid was washed with water. The aqueous phases were combined and acidified with 6N aqueous hydrochloric acid. The mixture was then extracted 3 times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness under vacuum.

Yield: 10.0g (76%)

R_fThe value: 0.47 (RP-8; methanol/5% sodium chloride solution 6:4)

C₁₃H₁₅ClN₂O₄(298.72)

Mass spectrum: (M + H)⁺299/301 (isotope of chlorine)

(c) (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl) -amide

248mg (0.266mmol) 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline are added to a solution of 299mg (1mmol) of (2R, 4R) -1- (4-chloro-phenylcarbamoyl) -4-methoxy-pyrrolidine-2-carboxylic acid in 2ml THF and stirred for 30 min. Then, 162mg (1mmol) of 2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-ylamine was added, and the mixture was stirred at reflux temperature for 18 hours.

The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (eluent: DCM/(ethanol/ammonia 95:5)96:4-94: 6).

Yield: 15mg (3%)

R_fThe value: 0.41 (silica gel; dichloromethane/ethanol/ammonia ═ 90:10:1)

C₂₃H₂₇ClN₄O₃(442.94)

Mass spectrum: (M + H)⁺443/445 (isotope of chlorine)

The following compounds were prepared analogously:

example 4

(2S, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- [ (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (as trifluoroacetate salt)

(a) 1-tert-butyl-2-methyl (2S/R, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylate

21.4ml (1.6M in n-hexane, 34.2mmol) of an n-butyllithium solution are added dropwise to a solution of 4.8ml (34.2mmol) of diisopropylamine in 200ml of THF at-5 ℃ and stirred for 10 minutes. The mixture is subsequently cooled to-35 ℃ and mixed with a solution of 5.8g (22.4mmol) of 1-tert-butyl-2-methyl (2S, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylate in 200ml of THF. The mixture was heated to 0 ℃ over 1 hour and subsequently cooled to-78 ℃. 2.1ml (33.7mmol) of methyl iodide are added dropwise and the mixture is stirred at-78 ℃ for 4 hours. 3ml of a saturated ammonium chloride solution are then added dropwise and the mixture is warmed to room temperature. It was then mixed with water and extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel (DCM/MeOH4: 1).

Yield: 4.2g (69%)

R_fThe value: 0.38 (silica; dichloromethane/methanol 80:20)

C₁₃H₂₃NO₅(273.33)

Mass spectrum: (M + H)⁺＝274

(b) (2S/R, 4R) -4-methoxy-2-methyl-pyrrolidine-2-carboxylic acid methyl ester (trifluoroacetate)

800mg (293. mu. mol) of 1-tert-butyl-2-methyl (2S/R, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylate were dissolved in 2.5ml of DCM, mixed with 2.5ml of trifluoroacetic acid and stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness under vacuum.

Yield: quantification of

R_tThe value: 0.42 min (method B)

C₈H₁₅NO₃(173.21)

Mass spectrum: (M + H)⁺＝174

(c) 1-benzyl-2-methyl (2S, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylate

419mg (146. mu. mol) (2S/R, 4R) -4-methoxy-2-methyl-pyrrolidine-2-carboxylic acid methyl ester (as trifluoroacetate salt) are dissolved in 4.5ml DCM and admixed at 0 ℃ with 0.5ml (292. mu. mol) of DIPEA and subsequently with 0.3ml (175. mu. mol) of benzyl chloroformate. The mixture was stirred at 0 ℃ for 10 minutes and then at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and purified by RP-HPLC.

Yield: 114mg (50%)

R_tThe value: 1.37 minutes (method B)

C₁₆H₂₁NO₅(307.34)

Mass spectrum: (M + H)⁺＝308

The following were additionally obtained:

1-benzyl-2-methyl (2R, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylate

Yield: 114mg (50%)

R_tThe value: 1.41 minutes (method B)

C₁₆H₂₁NO₅(307.34)

Mass spectrum: (M + H)⁺＝308

(d) (2S, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylic acid 1-benzyl ester

114mg (370. mu. mol) of 1-benzyl-2-methyl (2S, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylate were dissolved in 1ml of methanol and mixed with 2.4ml (605. mu. mol) of 8% aqueous lithium hydroxide solution. The reaction mixture was stirred at room temperature for 3 days and then concentrated under vacuum. The residue was acidified with 1N HCl and extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.

Yield: 100mg (92%)

R_tThe value: 1.25 minutes (method B)

C₁₅H₁₉NO₅(437.54)

Mass spectrum: (M + H)⁺＝294

(e) (2S, 4R) -4-methoxy-2-methyl-2- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-ylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester (as trifluoroacetate salt)

56mg (345. mu. mol) of 1-benzyl (2S, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylate were dissolved in 0.5ml of DMF and mixed with 134mg (352. mu. mol) of HATU and 160. mu.l of NMM. The mixture was stirred at room temperature for 15 minutes, and then mixed with 100mg (341. mu. mol) of 2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-6-ylamine. The reaction mixture was stirred at room temperature for 3 hours and then acidified with trifluoroacetic acid. The product was isolated from the mixture by RP-HPLC.

Yield: 104mg (54%)

R_tThe value: 1.16 minutes (method B)

C₂₅H₃₁N₃O₄(437.54)×CF₃CO₂H

Mass spectrum: (M + H)⁺＝438

(f) (2S, 4R) -4-methoxy-2-methyl-pyrrolidine-2-carboxylic acid- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide as trifluoroacetic acid salt

104mg (345. mu. mol) of benzyl (2S, 4R) -4-methoxy-2-methyl-2- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-ylcarbamoyl) -pyrrolidine-1-carboxylate (as the trifluoroacetate salt) are dissolved in a mixture of 6ml of THF and 6ml of methanol, mixed with 30mg of palladium on carbon (10%) and hydrogenated with 3 bar of hydrogen for 2.5 h. The mixture was then filtered and concentrated under vacuum.

Yield: 75mg (96%)

R_tThe value: 0.32 minute (method B)

C₁₇H₂₅N₃O₂(303.41)×CF₃CO₂H

Mass spectrum: (M + H)⁺＝304

(g) (2S, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- [ (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (as trifluoroacetate salt)

75mg (180. mu. mol) (2S, 4R) -4-methoxy-2-methyl-pyrrolidine-2-carboxylic acid- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (as trifluoroacetate salt) are dissolved in 1.5ml DMF and mixed with 122. mu.l (796. mu. mol) NMM. Subsequently 30mg (195. mu. mol) of 4-chloro-phenyl isocyanate were added and the mixture was stirred at room temperature for 3 days. It was subsequently acidified with trifluoroacetic acid. The product was isolated from the mixture by RP-HPLC.

Yield: 62mg (60%)

R_tThe value: 1.17 minutes (method B)

C₂₄H₂₉ClN₄O₃(456.98)×CF₃CO₂H

Mass spectrum: (M + H)⁺457/459 (isotope of chlorine)

The following compounds were prepared analogously:

example 6

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (5-chloro-pyridin-2-yl) -amide ] -2- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (as trifluoroacetate salt)

(a) (2R, 4R) -4-methoxy-2- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-ylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester (as trifluoroacetate salt)

100mg (616. mu. mol) of 2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-ylamine are dissolved in 1.5ml of DCM and mixed at room temperature with 0.61ml (1.22mmol) of a trimethylaluminum solution (2M in toluene) and stirred for 15 minutes. The reaction mixture was added to 180mg (614. mu. mol) of 1-benzyl-2-methyl (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylate and washed with 0.5ml DCM. The reaction mixture was stirred at room temperature for 3 hours and then added to a 2N sodium hydroxide solution. The aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The residue was purified by RP-HPLC.

Yield: 169mg (51%)

R_tThe value: 1.05 minutes (method B)

C₂₄H₂₉N₃O₄(423.52)×CF₃CO₂H

Mass spectrum: (M + H)⁺＝424

(b) (2R, 4R) -4-methoxy-pyrrolidine-2-carboxylic acid- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (as trifluoroacetate salt)

168mg (313. mu. mol) of benzyl (2R, 4R) -4-methoxy-2- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-ylcarbamoyl) -pyrrolidine-1-carboxylate (as trifluoroacetate salt) are hydrogenated analogously to example 4 f.

Yield: 120mg (95%)

R_tThe value: 0.31 minute (method B)

C₁₆H₂₃N₃O₂(289.38)×CF₃CO₂H

Mass spectrum: (M + H)⁺＝290

(c) (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (5-chloro-pyridin-2-yl) -amide ] -2- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (as trifluoroacetate salt)

170mg (843. mu. mol) of 4-nitrophenylchloroformate are added to a solution of 100mg (778. mu. mol) of 2-amino-5-chloro-pyridine in 2ml of DCM and 70. mu.l (867. mu. mol) of pyridine, and the mixture is stirred for 3.5 hours. The reaction mixture was subsequently evaporated to dryness and added as crude product to a solution of 120mg (297 μmol) (2R, 4R) -4-methoxy-pyrrolidine-2-carboxylic acid- (2-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (as trifluoroacetate salt) and 125 μ l (900 μmol) TEA in 2.5ml DMF. The reaction mixture was stirred at room temperature for 3 days and then mixed with a saturated sodium bicarbonate solution. The aqueous phase was extracted 3 times with ethyl acetate.

The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The residue was purified by RP-HPLC.

Yield: 54mg (32%)

R_tThe value: 0.94 minute (method B)

C₂₂H₂₆ClN₅O₃(443.94)×CF₃CO₂H

Mass spectrum: (M + H)⁺444/446 (isotope of chlorine)

The following compounds can be prepared analogously:

example 11

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-bromo-phenyl) -amide ] -2- [ (2, 3-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (mixture of diastereomers)

(a) Acetic acid- (3-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide

2.2ml (31mmol) of dioxolane, 1.2g (9.6mmol) of piperidine hydrochloride, 1.78g (7.8mmol) of acetic acid- [3- (2-aminopropyl) phenyl]A mixture of amide and 5. mu.l of concentrated HCl was heated to 90 ℃ for 7.5 hours. After cooling, water and ethyl acetate were added, the aqueous phase was made basic with 2N NaOH and extracted 3 times with ethyl acetate. In the organic phase with Na₂SO₄After drying, the mixture is concentrated and purified by column chromatography (silica; CH)₂Cl₂/EtOH：NH₄OH95:5110/0->4/1) is purified.

R_fThe value: 0.15 (silica gel; dichloromethane/ethanol/NH)₄OH＝80:20:2)

C₁₂H₁₆N₂O(204.27)

Mass spectrum: (M + H)⁺＝205。

(b) Acetic acid- (2, 3-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide formate salt

0.71g (3.5mmol) of acetic acid- (3-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide in 2.0ml of formic acid are mixed with 0.31ml of 37% aqueous formalin at ambient temperature with stirring and stirred at 70 ℃ for 4.5 h. The reaction mixture was concentrated, ethanol was added several times, and the mixture was concentrated.

R_fThe value: 0.23 (silica gel; dichloromethane/ethanol/NH)₄OH＝80:20:2)

C₁₂H₁₆N₂O×CH₂O₂(264.32)

Mass spectrum: (M + H)⁺＝219。

(c) 6-amino-2, 3-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline dihydrochloride

0.98g (3.7mmol) of acetic acid- (2, 3-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide formate are mixed with a total of 15ml of 6N HCl over a period of several hours and stirred for a total of 16 hours. The reaction mixture was then concentrated under vacuum.

R_fThe value: 0.84 (RP-8; methanol/5% sodium chloride solution ═ 6:4)

C₁₁H₁₆N₂×2HCl(249.18)

Mass spectrum: (M + H)⁺＝177。

(d) (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-bromo-phenyl) -amide ] -2- [ (2, 3-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (mixture of diastereomers)

The title compound was prepared from 6-amino-2, 3-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline dihydrochloride and (2R, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylic acid 1-benzyl ester and 4-bromophenyl isocyanate according to the reaction sequence 4e, 4f, 4 g.

R_fThe value: 0.42 (RP-8; methanol/5% sodium chloride solution ═ 6:4)

C₂₄H₂₉BrN₄O₃(501.42)

Mass spectrum: (M + H)⁺501/503 (bromine isotope).

Examples 12 and 13

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-bromo-phenyl) -amide ] -2- [ (3S) - (2, 3-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide and (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-bromo-phenyl) -amide ] -2- [ (3R) - (2, 3-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide

The two pure stereoisomers can be prepared analogously to example 11. For this purpose, acetic acid- (3-methyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide is passed through a column with a chiral stationary phase (supercritical fluid chromatography: DAICEL-ADH column, 250 mm. times.20 mm; flow rate: 70 ml/min; eluent: supercritical CO)₂Methanol + 0.2% dimethylamine 87/13, enantiomer 1R_tThe value: 5.8 minutes; enantiomer 2R_tThe value: 6.7 min) was separated into its enantiomers by preparative column chromatography and the individual enantiomers were subsequently reacted according to the reaction sequence described in example 11 to prepare the title compound.

Diastereomer 1

R_fThe value: 0.39 (RP-8; methanol/5% sodium chloride solution ═ 6:4)

C₂₄H₂₉BrN₄O₃(501.42)

Mass spectrum: (M + H)⁺501/503 (bromine isotope)

Diastereomer 2

R_fThe value: 0.39 (RP-8;methanol/5% sodium chloride solution ═ 6:4)

C₂₄H₂₉BrN₄O₃(501.42)

Mass spectrum: (M + H)⁺501/503 (bromine isotope)

Example 14

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- [ (1, 2-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (mixture of diastereomers)

(a) (1-methyl-3, 4-dihydro-isoquinolin-6-yl) -carbamic acid methyl ester

A mixture of 4.13g (17.5mmol) of methyl N- [3- (2-methylcarbonylamino-ethyl) phenyl ] carbamate and 35ml of chloroform was slowly mixed with 8.00g (38.4mmol) of phosphorus pentachloride and the mixture was stirred for 16 hours. The mixture was then carefully poured into water and stirred for 45 minutes. It was extracted 3 times with dichloromethane and the aqueous phase was subsequently made basic with 4N NaOH. The precipitated crystals were suction filtered and dried.

Yield: 2.6g (68%)

Mass spectrum: (M + H)⁺＝219

(b) (1, 2-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -carbamic acid methyl ester

A mixture of 1.00g (4.5mmol) (1-methyl-3, 4-dihydro-isoquinolin-6-yl) -carbamic acid methyl ester, 2.3ml (37mmol) iodomethane and 25ml EtOAc was stirred for 72 h. The precipitated crystals are filtered off, dissolved in 10ml of methanol and 140mg (3.6mmol) of sodium borohydride are added in portions. After 2 h, the mixture was concentrated and purified by chromatography (silica gel; dichloromethane/methanol 90: 10).

Yield: 93 percent

Mass spectrum: (M + H)⁺＝236

R_tThe value: 0.78 min, method B

(c) 6-amino-1, 2-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline hydrobromide

A mixture of 110mg (0.47mmol) (1, 2-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -carbamic acid methyl ester, 2.0ml 33% HBr in glacial acetic acid and 2.0ml glacial acetic acid was heated to boiling for 1.5 h. The mixture was then concentrated under vacuum, mixed with water, the aqueous phase separated and freeze-dried.

Mass spectrum: (M + H)⁺＝177

R_tThe value: 0.28 min, method B

(d) (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide]-2- [ (1, 2-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide x CF₃COOH (mixture of diastereomers)

A mixture of 100mg 6-amino-1, 2-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline hydrobromide, 90mg (0.30mmol) (2R, 4R) -1- (4-chloro-phenylcarbamoyl) -4-methoxy-pyrrolidine-2-carboxylic acid and 0.25ml triethylamine in 5ml THF is slowly mixed with 0.71ml of a solution of 50% propanephosphonic acid cyclic anhydride (propanephosphonic acid cyclic anhydride) in ethyl acetate and heated to 75 ℃ for 3 hours. The reaction mixture was then concentrated in vacuo, acidified with trifluoroacetic acid and purified by chromatography.

R_tThe value: 1.13 minutes (method B)

C₂₄H₂₉ClN₄O₃(456.97)×CF₃CO₂H

Mass spectrum: (M + H)⁺457/459 (isotope of chlorine)

Examples 15 and 16

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-bromo-phenyl) -amide ] -2- [ (R) - (1, 2-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide and (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-bromo-phenyl) -amide ] -2- [ (S) - (1, 2-dimethyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide

The two pure stereoisomers can be prepared analogously to example 14. For this purpose, 6-amino-1, 2-dimethyl-1, 2, 3, 4-tetrahydro-isoquinoline hydrobromide was passed over a chiral stationary phase (DAICEL OJ-H, 250 mm. times.20 mm, 5. mu.M, hexane + 0.2% cyclohexylamine/isopropanol 60/40, flow rate 15 ml/min, enantiomer 1R_tThe value: 9.2 minutes; enantiomer 2R_tThe value: 14.1 min) was separated into enantiomers by preparative column chromatography and the individual enantiomers were subsequently reacted according to the reaction sequence described in example 14 to give the title compound.

Diastereomer 1

R_tThe value: 1.20 minutes (method B)

C₂₄H₂₉BrN₄O₃(501.42)×CF₃CO₂H

Mass spectrum: (M + H)⁺501/503 (bromine isotope)

Diastereomer 2

R_tThe value: 1.19 minutes (method B)

C₂₄H₂₉BrN₄O₃(501.42)×CF₃CO₂H

Mass spectrum: (M + H)⁺501/503 (bromine isotope)

Example 52

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- [ (2-methyl-1, 2, 3, 4-tetrahydro-8-aza-isoquinolin-6-yl) -amide

(a) 2-methyl-6-nitro-1, 2, 3, 4-tetrahydro-8-aza-isoquinoline

A mixture of 400mg (2.0mmol) 1-methyl-3, 5-dinitro-pyridone, 300mg 1-methyl-piperidin-3-one and 15ml2M ammonia in methanol was heated to 60 ℃ for 20 hours. It was concentrated and purified by chromatography (silica gel, CH)₂Cl₂/MeOH 98/2).

Yield: 15 percent of

R_tThe value: 0.25 minute (method B)

Mass spectrum: (M + H)⁺＝194

(b) 2-methyl-6-amino-1, 2, 3, 4-tetrahydro-8-aza-isoquinoline

A mixture of 75mg (0.311mmol) 2-methyl-6-nitro-1, 2, 3, 4-tetrahydro-8-aza-isoquinoline, 50mg Raney nickel and 10ml methanol was reduced under a hydrogen pressure of 3 bar for 4 hours. It is subsequently filtered and concentrated by evaporation.

Yield: quantification of

R_fThe value: 0.1 (silica gel; CH)₂Cl₂/methanol 9/1)

Mass spectrum: (M + H)⁺＝164

(c) (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide]-2- [ (2-methyl-1, 2, 3, 4-tetrahydro-8-aza-isoquinolin-6-yl) -amide x CF₃COOH

The title compound was obtained in analogy to example 14d from 2-methyl-6-amino-1, 2, 3, 4-tetrahydro-8-aza-isoquinoline.

R_tThe value: 1.03 minutes (method B)

C₂₂H₂₆ClN₅O₃(443.93)×CF₃CO₂H

Mass spectrum: (M + H)⁺444/446 (isotope of chlorine)

Example 53

(2R, 4R) -4-methoxy-2-methyl-pyrrolidine-1, 2-dicarboxylic acid-1- [ (5-chloro-pyridin-2-yl) -amide ] -2- [ (2-methyl-1, 2, 3, 4-tetrahydro-8-aza-isoquinolin-6-yl) -amide

The title compound was obtained in analogy to examples 6a, 6b, 6c from 2-methyl-6-amino-1, 2, 3, 4-tetrahydro-8-aza-isoquinoline.

R_tThe value: 0.96 minutes (method B)

C₂₂H₂₇ClN₆O₃(458.94)×CF₃CO₂H

Mass spectrum: (M + H)⁺459/461 (isotope of chlorine)

Example 54

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide]-2- [ (2-methyl-1, 2, 3, 4-tetrahydro-5-aza-isoquinolin-7-yl) -amide x CF₃COOH

In analogy to examples 52a and 52b, 2-methyl-7-amino-1, 2, 3, 4-tetrahydro-5-aza-isoquinoline was prepared from 1-methyl-3, 5-dinitro-pyridone and 1-methyl-piperidin-4-one and reacted according to example 14d to form the title compound.

R_tThe value: 0.99 min (method B)

C₂₂H₂₆ClN₅O₃(458.94)×CF₃CO₂H

Mass spectrum: (M + H)⁺444/446 (isotope of chlorine)

Example 55

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide]-2- [ (1, 2-dimethyl-1, 2, 3, 4-tetrahydro-8-aza-isoquinolin-6-yl) -amide xcf₃COOH

In analogy to example 52a, from 1-methyl-3, 5-dinitro-pyridone and 1-butoxycarbonyl-piperidin-2-methyl-3-one was prepared 1, 2-dimethyl-6-amino-1, 2, 3, 4-tetrahydro-8-aza-isoquinoline, followed by cleavage of the butoxycarbonyl group with trifluoroacetic acid, a Leukart-Wallach reaction according to example 11b and a nitro reduction in analogy to example 52b and a reaction according to example 14d to form the title compound.

R_tThe value: 1.07 minutes (method B)

C₂₂H₂₈ClN₅O₃(457.96)×CF₃CO₂H

Mass spectrum: (M + H)⁺458/460 (isotope of chlorine)

Example 56

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- [ (2-methyl-1, 2, 3, 4-tetrahydro-8-methoxycarbonyl-isoquinolin-6-yl) -amide

(a) 2-methyl-1, 2, 3, 4-tetrahydro-8-methoxycarbonyl-isoquinoline

Deprotection of 2-butoxycarbonyl-1, 2, 3, 4-tetrahydro-8-methoxycarbonyl-isoquinoline with HCl in methanol and subsequent methylation according to example 11 b.

R_tThe value: 0.84 minute (method B)

Mass spectrum: (M + H)⁺＝206

(b) 2-methyl-6-nitro-1, 2, 3, 4-tetrahydro-8-methoxycarbonyl-isoquinoline and regioisomers (regiooisomers)

A mixture of 1.04g (5.0mmol) 2-methyl-1, 2, 3, 4-tetrahydro-8-methoxycarbonyl-isoquinoline and sulfuric acid was slowly mixed with 0.57g potassium nitrate at-7 ℃ followed by stirring at-7 ℃ for 15 minutes and at ambient temperature for 1 hour. It was then slowly poured onto ice water and made basic with NaOH. The precipitated crystals are filtered off and dried. A mixture of regioisomers was obtained.

R_tThe value: 0.87 minute (method B)

Mass spectrum: (M + H)⁺＝251

(c) (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- [ (2-methyl-1, 2, 3, 4-tetrahydro-8-methoxycarbonyl-isoquinolin-6-yl) -amide

From 2-methyl-6-nitro-1, 2, 3, 4-tetrahydro-8-methoxycarbonyl-isoquinoline (mixed with regioisomers), the title compound was obtained by reduction of the nitro group with Pd/carbon followed by amide coupling of 2-methyl-6-nitro-1, 2, 3, 4-tetrahydro-8-methoxycarbonyl-isoquinoline according to example 14 d.

R_tThe value: 1.18 minutes (method B)

C₂₅H₂₉ClN₄O₅(500.98)×CF₃CO₂H

Mass spectrum: (M + H)⁺501/503 (isotope of chlorine)

Example 57

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- [ (2-methyl-4-methoxy-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (mixture of isomers)

(a) N-methyl-N- (4-nitrophenylmethyl) -2, 2-dimethoxy-ethylamine

A mixture of 1.56g N-methyl-N- (4-nitrobenzyl) amine in 40ml THF was mixed with 2.85ml of 45% solution of 2, 2-dimethoxyacetaldehyde in tert-butyl methyl ether. Followed by addition of 24mgp-TsOHx H₂O and 1.12ml of glacial acetic acid, and the mixture is stirred for 2 hours. 1.81g of sodium cyanoborohydride are subsequently added in portions and the mixture is stirred for a further 2 hours. 5ml of water was added to the mixture, which was then reduced to about 30% by volume by evaporation, the residue was mixed with water and extracted 3 times with EtOAc. The combined organic phases were washed with Na₂SO₄Drying, concentrating, and subjecting the crude product to chromatography (Alox; petroleum ether/EtOAc 8/2->7/3) is purified.

R_tThe value: 2.2 minutes (method D)

Mass spectrum: (M + H)⁺＝255

(b) 6-nitro-4-methoxy-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

A mixture of 0.83g N-methyl-N- (4-nitrophenylmethyl) -2, 2-dimethoxy-ethylamine and 3.0ml of trifluoromethanesulfonic acid was prepared in a dry ice/ethanol cooling bath, allowed to slowly rise to ambient temperature, and stirred for 18 hours. It was then poured onto ice water and made alkaline with 2N NaOH. Extracted 3 times with EtOAc and the organic phase was taken over Na₂SO₄Dried, concentrated and purified by repeated chromatography.

R_tThe value: 1.7 minutes (method D)

Mass spectrum: (M + H)⁺＝223

(c) 6-amino-4-methoxy-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline

A mixture of 6-nitro-4-methoxy-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline, 25mg Pd/carbon and 5.0ml MeOH was hydrogenated under a hydrogen pressure of 3 bar for 9 h. It is subsequently filtered and concentrated by evaporation.

Yield: quantification of

R_fThe value: 0.75 (RP-8; methanol/5% sodium chloride solution ═ 6:4)

Mass spectrum: (M + H)⁺＝193

(d) (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- [ (2-methyl-4-methoxy-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl) -amide (mixture of isomers)

The title compound was prepared according to example 4e from 6-amino-4-methoxy-2-methyl-1, 2, 3, 4-tetrahydro-isoquinoline and (2R, 4R) -1- (4-chloro-phenylcarbamoyl) -4-methoxy-pyrrolidine-2-carboxylic acid.

R_tThe value: 2.8 minutes (method D)

C₂₄H₂₉ClN₄O₄(472.96)×HCO₂H

Mass spectrum: (M + H)⁺473/475 (isotope of chlorine)

Example 58

(2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-bromo-phenyl) -amide ] -2- [ (2-methyl-5, 8-difluoro-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl) -amide x HCOOH

(a) 2-methyl-5, 8-difluoro-1, 2, 3, 4-tetrahydro-isoquinoline

The title compound was prepared according to example 11b from 5, 8-difluoro-1, 2, 3, 4-tetrahydro-isoquinoline.

R_tThe value: 1.6 minutes (method D)

Mass spectrum: (M + H)⁺＝184

(b) 2-methyl-5, 8-difluoro-7-nitro-1, 2, 3, 4-tetrahydro-isoquinoline

0.94g (5.1mmol) 2-methyl-5, 8-difluoro-1, 2, 3, 4-tetrahydro-isoquinoline with 2.8ml concentrated H₂SO₄Is slowly mixed with 0.36ml of 65% nitric acid. The mixture was then stirred under ice-cooling for 2.5 hours, and poured into ice water. It was made basic with NaOH, extracted 3 times with EtOAc and the organic phase was Na₂SO₄Dried, filtered and concentrated.

Mass spectrum: (M + H)⁺＝229

(c) (2R, 4R) -4-methoxy-pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-bromo-phenyl) -amide ] -2- [ (2-methyl-5, 8-difluoro-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl) -amide x HCOOH

The title compound was obtained from 2-methyl-5, 8-difluoro-7-nitro-1, 2, 3, 4-tetrahydro-isoquinoline in analogy to the synthetic sequence 52b, 14d leading to the title compound.

R_fThe value: 0.25 (silica gel; dichloromethane/ethanol/ammonia ═ 95:5:0.5)

C₂₃H₂₅BrF₂N₄O₃(523.36)×HCO₂H

Mass spectrum: (M + H)⁺523/525 (bromine isotope)

The following compounds can be prepared analogously to the above-described synthetic procedures or analogously to literature-known synthetic methods, from aniline and proline derivatives known in the literature or obtained by literature-known synthetic methods:

the following examples describe the preparation of pharmaceutical preparations containing any of the compounds of formula I as active substances.

Example A

Dry ampoules containing 75mg of active substance per 10ml

The components are as follows:

75.0mg of active substance

Mannitol 50.0mg

Adding water for injection to 10.0ml

Preparation:

the active substance and mannitol were dissolved in water. After encapsulation, the solution was freeze dried. The product was dissolved in water to produce a solution ready for injection.

Example B

Dry ampoules containing 35mg of active substance per 2ml

The components are as follows:

35.0mg of active substance

Mannitol 100.0mg

Adding water for injection to 2.0ml

Preparation:

the active substance and mannitol were dissolved in water. After encapsulation, the solution was freeze dried. The product was dissolved in water to produce a solution ready for injection.

Example C

Tablet containing 50mg of active substance

The components are as follows:

(1) active substance 50.0mg

(2) Lactose 98.0mg

(3) Corn starch 50.0mg

(4) Polyvinylpyrrolidone 15.0mg

(5) Magnesium stearate2.0mg

215.0mg

Preparation:

mixing (1), (2) and (3) and granulating with the aqueous solution of (4). Mixing the dried pellets of (5). From this mixture, a bi-planar tablet is compressed, with facets on both sides and a demarcation score on one side.

Tablet diameter: 9 mm.

Example D

Tablet containing 350mg of active substance

The components are as follows:

(1) active substance 350.0mg

(2) Lactose 136.0mg

(3) Corn starch 80.0mg

(4) Polyvinylpyrrolidone 3.0mg

(5) Magnesium stearate4.0mg

600.0mg

Preparation:

mixing (1), (2) and (3) together and granulating with the aqueous solution of (4). Mixing (5) into the dried pellets. From this mixture, a bi-planar tablet is compressed, with facets on both sides and a demarcation score on one side.

Tablet diameter: 12 mm.

Example E

Capsule containing 50mg of active substance

The components are as follows:

(1) active substance 50.0mg

(2) Dried corn starch 58.0mg

(3) Powdered lactose 50.0mg

(4) Magnesium stearate2.0mg

160.0mg

Preparation:

the preparation of (1) is carried out according to (3). This triturate was added to the mixture of (2) and (4) with vigorous mixing.

In the capsule filling machine, this powder mixture was filled into hard gelatin capsules No. 3.

Example F

Capsule containing 350mg of active substance

The components are as follows:

(1) active substance 350.0mg

(2) Dried corn starch 46.0mg

(3) Powdered lactose 30.0mg

(4) Magnesium stearate4.0mg

430.0mg

Preparation:

the preparation of (1) is carried out according to (3). This triturate was added to the mixture of (2) and (4) with vigorous mixing.

In the capsule filling machine, this powder mixture was filled into hard gelatin capsules No. 0.

Example G

Suppository containing 100mg of active substance

1 suppository contains:

active substance 100.0mg

Polyethylene glycol (M.W.1500) 600.0mg

Polyethylene glycol (M.W.6000) 460.0mg

Polyethylene sorbitan monostearate840.0mg

2000.0mg

Preparation:

polyethylene glycol was melted with polyethylene sorbitan monostearate. The milled active was homogeneously dispersed in the melt at 40 ℃. It is cooled to 38 ℃ and poured into a slightly cooled suppository mold.

Claims (12)

1. Compounds of general formula (I), tautomers, enantiomers, diastereomers and salts thereof

Wherein

D represents a substituted bicyclic ring system of formula

Wherein

K¹

represents-CH₂、-CHR^7a、-CR^7bR^7cOr a group-C (O), and wherein

R^7a/R^7b/R^7c

Each independently of the others represents a fluorine atom, a hydroxyl group, C_1-5-alkoxy, C_1-5-alkyl, wherein except-C (R)^7bR^7c) -corresponds to-CF₂Radicals, otherwise two radicals R^7b/R^7cNot all being bound to a ring carbon atom via a heteroatom at the same time, or

Two radicals R^7b/R^7cTogether with the ring carbon atoms may form a 3-membered carbocyclic group,

K²and K³

Each independently of the other represents-CH₂、-CHR^8a、-CR^8bR^8cOr a group-C (O) -wherein

R^8a/R^8b/R^8c

Each independently of the other represents C_1-5-alkyl, and/or

Two radicals R^8b/R^8cTogether with the ring carbon atoms, may form a 3-membered saturated carbocyclic group,

and

in total, there may be no more than 4R selected from^7a、R^7b、R^7c、R^8a、R^8bAnd R^8cA group of

X represents an oxygen or sulfur atom, a sulfoxide, a sulfone, -CF₂-or NR¹Group (a) in which

R¹Represents a hydrogen atom or a hydroxyl group, C_1-3Alkoxy, amino, C_1-3Alkylamino, di- (C)_1-3-alkyl) -amino, C_1-5Alkyl radical, C_2-5-alkenyl-CH₂、C_2-5-alkynyl-CH₂Or C_3-6-a cycloalkyl group,

and wherein

A¹Represents N or CR¹⁰，

A²Represents N or CR¹¹，

A³Represents N or CR¹²，

Wherein R is¹⁰、R¹¹And R¹²Each independently of the other represents:

hydrogen, fluorine, chlorine, bromine or iodine atom, or C_1-5-alkyl, CF₃Cyano, carboxyl, C_1-5Alkoxycarbonyl, hydroxy, C_1-3-alkoxy, CF₃O、CHF₂O、CH₂FO, amino, C_1-5Alkylamino, di- (C)_1-5-alkyl) -amino or C_4-7-cycloalkylideneimino

-L-E-G-J-represents a-C or-C ═ C-C group, which may be substituted by R⁴And R⁵Is substituted, and

R³represents a hydrogen atom or C_1-3-alkyl, and

R⁴represents a hydrogen atom or

Straight or branched C_1-6-an alkyl group,

wherein C is linear or branched_1-6-the hydrogen atoms of the methylene and/or methyl fragments of the alkyl group are optionally substituted independently of each other by substituents selected from the group consisting of: hydroxy, C_1-5Alkoxy, carboxyl, C_1-5-an alkoxycarbonyl group, a carbonyl group,

and is

if-L-E-G-J-represents a-C-C-C-group and R⁴To E or G, then R⁴May also represent fluorine atom or hydroxyl, methoxy, C_3-5-alkenyl-oxy, C_2-5-alkyl-oxy, C_3-6-cycloalkyl-oxy, C_1-5-alkylaminocarbonyloxy, di (C)_1-5-alkyl) aminocarbonyloxy or C_4-7-a cycloalkyleneiminocarbonyloxy group,

the conditions are as follows except:

CH in which the two heteroatoms selected from oxygen and nitrogen are exactly one optionally substituted₂The radicals being separate from one another, and

R⁵represents a hydrogen atom, C_1-5Alkyl, allyl or benzylOr if R is⁵Attached to E or G, it may also represent hydroxy or methoxy, or

R⁴And R⁵If they are bound to the same carbon atom, they may form, together with the carbon atom, a-C ═ O group or-CF₂A group of, or

R⁴And R⁵If they are attached to the same carbon atom or two adjacent carbon atoms, they together with the carbon atoms may form a 3-to 6-membered carbocyclic group,

wherein C is_5-6Four directly adjacent carbon chain members of the carbocyclic group may be taken together by-O-CH₂-CH₂-a substitution of the O group,

or fragments thereof

Represents a group

R¹³Represents a hydrogen atom or C_1-5-an alkyl group,

m represents optionally substituted R²And R⁶A substituted benzene, thiophene or pyridine ring, wherein

R²Represents a fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, vinyl, methoxy, ethynyl, cyano or-C (O) NH group₂Group (a) and

R⁶represents a hydrogen, fluorine, chlorine, bromine or iodine atom or a hydroxyl, methoxy, trifluoromethoxy, C optionally substituted by a fluorine atom_1-3-alkyl, cyano, amino or NH₂A group of C (O),

and wherein the alkyl, alkenyl, alkynyl and alkoxy groups contained in the above definitions having two or more carbon atoms may be straight-chain or branched, and the alkyl groups in the above dialkylating groups such as dialkylamino group may be the same or different,

and the hydrogen atoms contained in the methyl or ethyl group in the above definition may be replaced in whole or in part by fluorine atoms.

2. A compound of general formula (I), its tautomers, enantiomers, diastereomers and salts according to claim 1, wherein

X represents NR¹Group (a) in which

R¹Represents a hydrogen atom or C_1-5-alkyl, allyl or cyclopropyl, and

A¹represents CR¹⁰，

A²Represents CR¹¹，

A³Represents N or CR¹²，

Wherein R is¹⁰、R¹¹And R¹²Each independently of the other represents:

hydrogen, fluorine or chlorine atoms, or methyl, CF₃Cyano, carboxyl, C_1-5Alkoxycarbonyl, hydroxy, methoxy, CF₃O、CHF₂O、CH₂FO group.

3. A compound of general formula (I), its tautomers, enantiomers, diastereomers and salts according to claim 1, wherein

-L-E-G-J-represents a-C-C-C-C group which may be substituted by R as defined above in claim 1⁴And R⁵And (4) substitution.

4. A compound of general formula (I), its tautomers, enantiomers, diastereomers and salts according to claim 1, wherein

D represents a substituted bicyclic ring system of the formula

Wherein

K¹represents-CH₂、-CHR^7a、-CR^7bR^7cOr a group-C (O), wherein

R^7aIs represented by C_1-2An alkyl group, a carboxyl group,

R^7b/R^7ceach independently of the others represents hydroxy, methoxy or C_1-3-an alkyl group,

in which two radicals R^7b/R^7cNot bound to a ring carbon atom via an oxygen atom at the same time, or two radicals R^7b/R^7cTogether with the ring carbon atoms may form a 3-membered carbocyclic group,

and

K²and K³In each case independently of one another:

-CH₂、-CHR^8aor-CR^8bR^8cGroup (a) in which

R^8a/R^8b/R^8c

Each independently of the other represents C_1-3-alkyl, and/or

Two radicals R^8b/R^8cTogether with the ring carbon atoms, may form a 3-membered saturated carbocyclic group,

and

in total, there may be no more than 4R selected from^7a、R^7b、R^7c、R^8a、R^8bAnd R^8cA group of

X represents NR¹Group (a) in which

R¹Represents a hydrogen atom or C_1-3-alkyl, allyl or cyclopropyl, and

A¹represents CR¹⁰，

A²Represents CR¹¹，

A³Represents CR¹²，

Wherein R is¹⁰、R¹¹And R¹²Each independently of the other represents:

hydrogen, fluorine or chlorine atoms, or methyl, CF₃Hydroxy, methoxy, CF₃O、CHF₂O、CH₂The radical FO is a radical of,

and

-L-E-G-J-represents a-C-C-C-C group, which may be substituted by R⁴And R⁵Is substituted, and

R³represents a hydrogen atom, an

R⁴Represents a hydrogen atom or

Straight or branched C_1-3-an alkyl group,

wherein C is linear or branched_1-6-the hydrogen atoms of the methylene and/or methyl fragments of the alkyl group are optionally substituted independently of each other by substituents selected from the group consisting of: hydroxy, C_1-5Alkoxy, carboxyl, C_1-5-alkoxycarbonyl, or

If R is⁴Attached to E or G, it may also represent a fluorine atom or a hydroxyl, methoxy, C_3-5-alkenyl-oxy, C_2-5-alkyl-oxy, C_3-6-cycloalkyl-oxy, C_1-5-alkylaminocarbonyloxy, di (C)_1-5-alkyl) aminocarbonyloxy or C_4-7-a cycloalkyleneiminocarbonyloxy group,

provided that the following cases are excluded

CH in which the two heteroatoms selected from oxygen and nitrogen are exactly one optionally substituted₂The radicals being separate from one another, and

R⁵represents a hydrogen atom or C_1-5-alkyl, allyl or benzyl, or if R⁵Attached to E or G, it may also represent hydroxy or methoxy, or

R⁴And R⁵If they are bound to the same carbon atom, they may form, together with the carbon atom, a-C ═ O group or-CF₂A group of, or

R⁴And R⁵If they are attached to the same carbon atom or two adjacent carbon atoms, they together with said carbon atoms may form a 3-to 6-membered carbocyclic group,

wherein C is_5-6Four directly adjacent carbon chain members of the carbocyclic group may be taken together by-O-CH₂-CH₂The substitution of the O group is carried out,

R¹³represents a hydrogen atom, and is represented by,

m represents a radical R at the 4 position²Substituted benzene rings or by R in the 5-position²A substituted pyridine ring, wherein

R²Represents a fluorine, chlorine, bromine atom, methoxy group or ethynyl group, and

R⁶represents a hydrogen or fluorine atom.

5. A compound of general formula (I), its tautomers, enantiomers, diastereomers and salts according to claim 1, wherein the central ring is

To represent

6. A compound of general formula (I), its tautomers, enantiomers, diastereomers and salts according to claim 1, wherein

D represents a substituted bicyclic ring system of the formula

7. Compounds of general formula (I) according to claim 1, their tautomers, enantiomers, diastereomers and salts, which have the chain members G and L of the central ring in 5-membered ring in the R configuration.

8. A compound selected from:

or (R) -pyrrolidine-1, 2-dicarboxylic acid-1- [ (4-chloro-phenyl) -amide ] -2- (1-oxo-1, 2, 3, 4-tetrahydro-isoquinolin-7-yl) -amide,

and tautomers, enantiomers, diastereomers and salts thereof.

9. A physiologically acceptable salt of a compound according to any one of claims 1 to 8.

10. A medicament containing a compound according to any one of claims 1 to 8 or a physiologically acceptable salt according to claim 9, optionally together with one or more inert carriers and/or diluents.

11. Use of a compound according to any one of claims 1 to 8 or a physiologically acceptable salt according to claim 9 for the preparation of a medicament having an inhibitory effect on factor Xa and/or an inhibitory effect on a related serine protease.

12. Process for the preparation of a medicament according to claim 10, characterized in that a compound according to any one of claims 1 to 8 or a physiologically acceptable salt according to claim 9 is incorporated by non-chemical means into one or more inert carriers and/or diluents.